(1) Field of the Invention
This invention relates to new depsipeptide antibiotics, called neoviridogriseins I, II and III; to their production and isolation; and to their utilization as therapeutic drugs and animal feed additive.
(2) Description of the Prior Art
The mikamycin-vernamycin (or streptogramin) family of antibiotics are classified into two major groups. One major group (Group A according to D. Vazquez; pp521-534, ANTIBIOTICS III, Mechanism of action of antimicrobial and antitumor agents, Springer-Verlag Berlin Heidelberg New York 1975) is a macrocyclic lactone compound, and includes griseoviridin, ostreogrycin A(=mikamycin A=virginiamycin M=staphylomycin M=pristinamycin IIA=vernamycin A=streptogramin A=synergistin A-1=Compound PA-114A1=Compound E-129 Factor A, etc.), ostreogrycin G (=virginiamycin MII=staphylomycin MII=pristinamycin IIB=dihydrostreogrycin A=Compound E-129 Factor B=Compound R.P.-13920, etc.), and Compounds A-2315 A, B and C. Though bacteriostatic, this group of antibiotics are active against Gram-positive bacteria and mycoplasmas. Griseoviridin, which is one of the fermentation products in this invention, is known to be produced together with viridogrisein by streptomycetes, and the production of griseoviridin is disclosed in U.S. Pat. Nos. 3,023,204 and 3,174,902. The other major group (Group B according to D. Vazquez) is a macrocyclic depsipeptide compound and divided into two sub-groups, that is, the viridogrisein sub-group and the vernamycin B sub-group. The antibiotics in this major group are mainly effective in suppressing the growth of Gram-positive bacteria such as Staphylococcus aureus and Bacillus subtilis. The vernamycin B sub-group contains 12 homologues. Because the synonym relationships among the published names of antibiotics in this group are so complicated, it is practically impossible to list all the compound names of this sub-group. Some representative, and scientifically important, compounds of this sub-group are as follows:
1. Vernamycin B=ostreogrycin B=pristinamycin IA=mikamycin B=streptogramin B=synergistin B-1=compound E-129 Factor Z=compound PA114B1. PA0 2. Vernamycin B=ostreogrycin B1=pristinamycin IC=compound E-129 Factor Z1. PA0 3. Vernamycin B=ostreogrycin B2=pristinamycin IB=compound E-129 Factor Z2=compound R.P.-13919. PA0 4. Ostreogrycin B3=compound E-129 Factor Z3. PA0 5. Patricin A PA0 6. Patricin B PA0 7. Vernamycin B.sub..delta. PA0 8. Vernamycin C=doricin PA0 9. Virginiamycin (Staphylomycin)S PA0 10. Virginiamycin(Staphylomycin)S2 PA0 11. Virginiamycin (Staphylomycin)S3 PA0 12. Virginiamycin (Staphylomycin)S4 (or S1) PA0 (1) Sucrose-nitrate agar PA0 (2) Glucose-asparagine agar PA0 (3) Glycerin-asparagine agar PA0 (4) Yeast extract-malt extract agar PA0 (5) Starch agar PA0 (6) Tyrosine agar PA0 (7) Nutrient agar PA0 (8) Oatmeal agar PA0 Positive: D-Xylose, D-glucose, D-fructose L-rhamnose, D-mannitol. PA0 Slightly positive: Sucrose. PA0 Negative: L-Arabinose, i-inositol, raffinose. PA0 Streptomyces griseus NRRL 2426 PA0 (1) Silica gel TLC PA0 (2) Cellulose TLC PA0 Neoviridogrisein II: 27% PA0 Neoviridogrisein IV(viridogrisein): 23% PA0 Griseoviridin: 50% PA0 Neoviridogrisein II: 25% PA0 Neoviridogrisein IV (viridogrisein): 25% PA0 Griseoviridin: 50% PA0 Strain: MIC PA0 Mycoplasma gallisepticum KP13: 0.07 PA0 Mycoplasma pulmonis: 0.20 PA0 Mycoplasma fermentans: 0.05 PA0 Mycoplasma agalactiae: 0.05 PA0 Neoviridogrisein II: 27% PA0 Neoviridogrisein IV (viridogrisein): 23% PA0 Griseoviridin: 50%
The compounds of this sub-group have the common feature that they are composed of seven constituents sharing in the same four constituents of 3-hydroxypicolinic acid, L-threonine, L-proline and L-phenylglycine. On the other hand, in the viridogrisein sub-group there has been known only one compound, viridogrisein, and the identity with viridogrisein of etamycin, compound K-179 and compound F-1307A is well established. In contrast to the above vernamycin B sub-group, viridogrisein is composed of 8 constituents, that is, 3-hydroxypicolinic acid, L-threonine, D-leucine, 4-hydroxy-D-proline, sarcosine, .beta.,N-dimethyl-L-leucine, L-alanine and L-phenylsarcosine. As apparent in the following detailed description of the invention, the neoviridogrisein antibiotics of this invention belong to this viridogrisein sub-group, and one of the compounds, neoviridogrisein IV, has been identified as viridogrisein. Preparation of viridogrisein is disclosed in U.S. Pat. No. 3,023,204.
The synergism between Group A and Group B is well known on various microorganisms, and profitably utilized to potentiate the therapeutic efficiency of pharmaceutical drugs containing the antibiotic of this family as active components. This is true of neoviridogriseins, too.